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Title: The role of postsynaptic density protein 95 (PSD-95) in excitatory signalling
Author: Vickers, Catherine
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2005
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The major receptor for excitatory neurotransmission in the central nervous system is the n-methyl-D-aspartate (NMDA) receptor. Recent study has shown that this receptor can be linked to networks of signalling proteins through binding to a scaffolding protein. Postsynaptic Density Protein 95 (PSD-95). This complex of proteins is termed the NMDA receptor complex (NRC). This thesis examined the role of PSD-95 in excitatory signalling and synaptic plasticity throughout the brain, with particular focus on the corticostriatal system. A proteomic approach was used to assess the expression levels of proteins in the NRC throughout specific regions of the mouse brain in wild type and PSD-95 mutants. Analysis revealed there to be no difference in expression levels of associated proteins within the forebrain (striatum, hippocampus and context) of wild type animals, but that the cerebellum showed expression levels that differed to the other areas. However, analysis of mice with a mutation in PSD-95 revealed there to be alterations in the expression levels and phosphorylation states of NRC associated proteins. These proteins were altered throughout the forebrain regions analysed, along with the cerebellum. They included proteins known to be important in NMDA receptor dependant signalling and synaptic plasticity. Moreover, analysis of expression levels of specific NRC associated proteins believed to have roles in focal ischaemia, revealed further alterations in PSD-95 mutant mice that had been subjected to focal ischaemia. The final set of experiments addressed the role of PSD-95 in corticostriatal synaptic plasticity. Electrophysiological recordings from striatal spiny cells revealed no strong phenotype in the PSD-95 mutant mouse with regard to alterations in excitatory postsynaptic potential (EPSP) amplitude post trains of cortical stimulation. The data reveal that PSD-95 is important in several aspects of neuronal connectivity, but that its effects can be specific to different areas of the brain. Moreover, the data suggest that the removal of an important protein from a signalling network can affect other signalling molecules within the same network.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available